This competitive renewal seeks support to continue our work on a-adrenergic modulation of resting and acute food-intake related energy expenditure (EE) with primary human aging. In the first set of specific aims we propose to establish the integrative sympathoadrena1 a-adrenergic mechanisms responsible for the reductions in body composition-adjusted resting metabolic rate (RMRadj) and the thermic effect of food (TEF-the postprandial increase in EE in response to acute energy intake) that occur with advancing age. In the second set of specific aims we propose to determine the integrative sympathoadrenal a-adrenergic mechanisms responsible for the greater RMRadj: and TEF in habitually exercising vs. sedentary middle-aged and older adults[unreadable] In the third set of specific aims we propose to determine the role of a2-adrenergic receptor gene variants in explaining inter-individual differences in a-adrenergic modulation of RMRadj and TEF in general, and specifically with advancing age. To test these hypotheses and achieve the associated specific aims we will use a novel translational experimental approach that attempts to link age- and habitual exercise-related group differences in EE (RMRadj; TEF) with systemic (tonic a-adrenergic modulation of metabolic rate; a-adrenergic stimulation of postprandial thermogenesis; sympathoadrenal system activity; metabolic responsiveness to a- adrenergic stimulation), cellular/molecular (a-adrenergic receptor and post-receptor signaling properties), and genetic (a2-adrenergic receptor gene variants) in healthy adult humans. The proposed research should provide new and clinically important insight into the separate and interactive effects of aging and habitual exercise on a- adrenergic modulation of EE, with important implications for the prevention of age-associated obesity. The proposed research also will provide novel insight into the integrative (whole-body to molecular/genetic) physiological mechanisms underlying these effects.